Effects of bisphosphonic acids on the skeletal system have been known for years. The inhibition of osteo-resorption due to an intake of the substances considered in rats has been published in Acta. Endocrinol. 76, 613 (1976) as well as the retardation of chronic arthritis progression in Brit. J. Pharmacology 21, 127 (1963). Patent literature describes the effect of 1-hydroxy-1,1-ethylidenebisphosphonic acid (U.S. Pat. No. 3,683,080/1972) and of 3-amino-1-hydroxy-1,1-propylidenebisphosphonic acid (DE Pat. 2 405 254/1974) on calcium metabolism, resp. The therapy of urolithiasis and osteo-resorption inhibition with 4-amino-1-hydroxy-1,1-butylidenebisphosphonic acid is described in U.S. Pat. No. 4,621,077 (1984).
Numerous patents also provide the information concerning the pharmaceutical formulations with the compounds above stated. For example, the composition of the pharmaceutical formulation consisting of 3-amino-1-hydroxy-1,1-propylidenebisphosphonic acid together with lactose, starch, and magnesium stearate for the tablet dosage form or together with lauryl sulphate for the capsule form is given in DE Pat. 24 05 524 (1974). The pharmaceutical formulation of bisphosphonic acids not specified particularly is registered by the patent EP 550 395 (1991) even if again lactose, starch, and stearic acid are shown as an example. The patent EP 274 158 (1986) claims for the rights on a family of bisphosphonates including heterocyclic substituent relating to the capsule (starch, lauryl sulphate) and tablet (lactose, starch, magnesium stearate) pharmaceutical forms. In the patent EP 600 834 (1992) covering the use of bisphosphonic acids that are already registered by the patent EP 550 392 above stated for fracture treatment the following pharmaceutical forms orally administered are specified: pellets with the core formed by the active ingredient and microcrystalline cellulose; tablets containing lactose, starch, gelatine, talc, magnesium stearate, and silicon dioxide.
The pharmaceutical dosage form specifically related to 4-amino-1-hydroxy-1,1-butylidenebisphosphonic acid (hereinafter “alendronic acid”) and to its salts is described in Rosini's patent U.S. Pat. No. 4,621,077 (1984) including the examples of 10-mg and 20-mg formulations:
SubstancemgmgSodium alendronate2512.5Lactose8480Hydrolysed starch55Talc58.5Magnesium stearate11
The international patent application WO 95/29679 describes the process of manufacture of medicinal products containing alendronic acid salts based on the wet granulation. Such a process consists in mixing of the active ingredient and diluent to form a damp powder mass that is processed into granules by the wet granulation (e.g. in a planet granulator). The granules formed are dried, milled to a standard particle size, and blended with the disintegrating agent and the lubricant. After a final mixing the pre-compression mixture is compressed into the specified tablet form. Considering the composition given as the examples most tablets thus produced consist of lactose, microcrystalline cellulose, magnesium stearate, and of sodium salt of crosscarmellose. Apart from lactose the patent describes use of other diluents like calcium phosphate, mannitol, pulverised cellulose, pregelatinized starch, or microcrystalline cellulose. As a specifically preferred composition of diluents, a mixture of lactose and microcrystalline cellulose is mentioned. Lactose is known to be able to interact with sodium alendronate, especially in the presence of water, and to hasten its degradation. Microcrystalline cellulose is chemically inert towards alendronic acid, but it is somewhat hygroscopic, which again increases the amount of moisture and the possibility of interactions between lactose and the active ingredient. A granulation, let it be dry or wet, is an additional step of every technological process in comparison with direct compression. It makes possible to compress such mixtures that would not provide the requisite quality of the tablet in direct compression. On the other hand, especially wet granulation wherein the product is moistened and heated, forms unfavourable conditions for more sensitive organic substances.
Owing to its very appropriate compression characteristics lactose is undoubtedly a diluent of the widest use, but it still exhibits some objectionable properties. It browns frequently in the environment displaying high relative humidity (more than 80%). Moreover, this process accelerated by a heat is not reproducible with respect to the particular lactose kind (content of micro-impurities may be concerned). When the active ingredients including the primary amine group are applied, Maillard's reaction [L. C. Maillard: Compt.Rend. 154, 66 (1912)] accelerated by alkaline agents may take place and bring a medicinal product to get brown including a decrease of its active ingredient content. Therefore, lactose is not recommended to be applied to the preparation of medicinal products that contain primary amine groups, as it is the case of a majority of therapeutically efficient bisphosphonic acids.
An answer to the issue of bisphosphonic acids-lactose formulation seeks WO 94/12200 of the MSD Company. This patent application refers to the formulation and to the process of manufacture of medicinal products based on bisphosphonic acids using the direct compression process technology. As may be apparent from the document considered the tablet contains, in addition to the active ingredient, a diluent in the form of anhydrous or hydrated lactose, a dry binder, a disintegrating agent, and a lubricant. Characteristic features of the direct compression process described in the inventory above mentioned are, as follows:
Composition: active ingredient, anhydrous lactose, microcrystalline cellulose, magnesium stearate, and sodium salt of carmellose (carboxymethylcellulose).
Process of manufacture: The active ingredient is first blended with one-third of microcrystalline cellulose and with one-half of anhydrous lactose. The pre-mixture obtained is then blended with both remaining excipients and it is mixed again. Sodium salt of carmellose is added under mixing to be followed with magnesium stearate to finish the mixture blending. When homogenized the mixture is subjected to compression.
The described process avoids the rather lengthy and uneconomical manufacturing process involving granulation.
As may be apparent from the results of comparative testing of the finished product stability performed at the temperature of 40° C. and relative humidity of 75% described in the patent application considered the process exhibiting a greater simplicity and economy provides the product of a higher stability. A sealed pack of the medicinal product produced by the direct compression still contains 98.5% of alendronate original quantity after three months as compared with 94.6% of alendronate in the granulated product. A lower product stability relating to the wet granulation is to be rectified by a drying agent; its presence in the granulated product has ensured alendronate content at the level of 99.7% after the stability testing.
The problem of product instability related to Maillard's reaction has not been quite solved by this measure either. A hygroscopic behaviour is encountered in the substances actually contained in the tablet (lactose, cellulose, carmellose; for details see Handbook of Pharmaceutical Excipients 1994, Editor: American Pharmaceutical Association, for example), and so, the medicinal product concerned sealed in common packs without desiccants absorbs atmospheric humidity progressively and its declared two-year stability under humid and warm storage conditions is very questionable on that account.
The patent application WO 99/04773, concerning the method of osteo-resorption inhibition based on once or twice a week dosage schedule, or, possibly, on one dose in a fortnight, claims also for the pharmaceutical compositions containing 70 mg or 140 mg of alendronic acid. The formulation actually described in the patent application considered fully corresponds to that of the patent application WO 94/12200, discussed above:
SubstancemgSodium alendronate45.68Lactose71.32Microcrystalline cellulose80Crosscarmellose2Magnesium stearate1
It is evident from the review above given that the patent literature does not involve any excipient combination providing the full and adequate solution of the tablet formulation containing alendronic acid.
The theoretical approach to the discussed issue consists in a substitution of lactose with other diluents as may be, for example:
a) Mannitol
Mannitol is one of typical diluents applied to the preparation of tablets containing humidity-sensitive substances. Because it does not undergo Maillard's reaction (it does not include glycoside hydroxygroup) it suits the formulation with amines or amino acids, including aminobisphosphonic acids. Owing to its exclusive stability he serves as the additive in injection products containing aminobisphosphates.
The medicinal products containing lactose provided with a common package are not able to exhibit the adequate stability for a reasonable time period in highly humid surroundings of above 90-% relative humidity. Moreover, the products including amino acids are susceptible to Maillard's reaction under such humidity conditions. Instability of the products with mannitol due to excessive water content is obvious only at the relative humidity exceeding 98%.
Background experience relating to mannitol application in practice is quite well, especially as far as the wet granulation is concerned. However, mannitol use in case of the direct compression is not advisable due to its inferior compression characteristics.
b) Calcium Hydrogen Phosphate
Calcium hydrogen phosphate is another very stable diluent that fits to the mixtures processed by the direct compression. It possesses the desirable properties of high stability and compressibility but a certain alkalinity that may adversely affect the product stability belongs to its drawbacks.
c) Microcrystalline Cellulose
Microcrystalline cellulose (MCC) is to be used in the formulations prepared by the direct compression as the solid binder of a considerable effect on overall compression characteristics of a tablet. The increasing MCC content in a formulation results in lowering the requirements for the compressibility of a diluent. In some cases MCC is able to replace the diluent completely. MCC hygroscopicity may adversely affect the finished product stability.
d) Modified Starches
They provide another possibility as far as choice of the fillers of the formulations considered is concerned. Hygroscopicity of modified starches may adversely affect the finished product stability.
All the above cases concern agents that, unlike disaccharides of the lactose type, are not incompatible with aminophosphates of the type of alendronic acid. However, the degree of their stability and compression characteristics differ from case to case.
In experts' view the replacement of lactose with other diluent is less advisable. Such a position is to be explained by inferior compression properties of the substance concerned usually encountered. Diluents used in the formulation prepared by direct compression are often blamed for their inadequate compressibility that makes necessary the high-pressure compression machines to be applied to attain an appropriate hardness of the medicinal product. However, such a modification results in lower recovery of a tablet content and, consequently, in demand to use special and expensive disintegrating agents as sodium salt of carmellose above mentioned may be, for example. In some cases the direct compressed mixture may exhibit poor flow characteristics that may impair the adequate control on the tablet mass and, possibly, an efficient utilization of the fall capacity of sophisticated compression machines. A pre-compression mixture flow characteristics are often ameliorated by adding of stearates. Magnesium stearate is used for such a purpose most frequently.
The strong points of lactose as the diluent in formulations prepared by direct compression and apparent unsuitability of other diluents are best illustrated by their compression characteristics and equilibrium water content (adsorption isotherm) presented as the example.
A comparison of the compression characteristics of mannitol, cellulose, and of lactose is given e.g. in Handbook of Pharmaceutical Excipients
Considering the compared substances mannitol granulate seems to be the most unsuitable for the direct compression because the increase of compression above 12 kN does not provide any increase in the tablet hardness dissimilar to lactose where the tablet hardness increases almost proportionally to the compression. This outcome is of a considerable importance in relation to a control of tablet quality. Compression characteristics of cellulose are practically identical with those of lactose over the whole range of compression values under examination.
A second significant parameter is a hygroscopicity of the substance considered.
Taking the hygroscopic properties of the compared substances into account mannitol seems to be the best diluent because its moisture starts to rise at about 98-% relative humidity. Lactose is very appropriate diluent even in relation to atmospheric humidity absorption because a significant increase in the water content is apparent above 90-% relative humidity of the air. Cellulose absorbs a relevant water quantity at 70-% atmospheric humidity already. The poor stability of the products containing the diluents examined is to be expected only in case of cellulose application, the best and very good one is related to mannitol and lactose use, resp.
These facts indicate that lactose integrates two characteristics of decisive importance for preparation of the tablets displaying a good quality and adequate stability. It is to be assumed accordingly that lactose replacement with other diluents is to bring about a deterioration of the product quality.
For example, mannitol is used when the relevant process of manufacture involving granulation does not rely on any particular parameters of the compression characteristics of excipients concerned as above shown. Microcrystalline cellulose, hydrogen phosphates, or starches enter the process as binders in smaller amounts and they are proposed to serve as diluents as well.
A deterioration of the product quality of a diverse extent for different active ingredients has to be taken into account in case of lactose replacement with another diluent. In general, it is not to be envisaged whether qualitative data relating to the product specified in a relevant pharmacopoeia will be met and the tablet will be ever used. It can be further assumed that where such quality is obtainable it will be necessary to find the specific composition in a relatively laborious optimization process.
The review of present state of the art in the field of techniques concerned indicates lactose, although entering into the chemical reaction with alendronate, to be an exceptionally suitable diluent integrating both an adequate stability (with the exception of very humid conditions where mannitol shows a higher stability) and good compressibility (similar to microcrystalline cellulose). Based on the adopted chart of compressibility and of adsorption isotherm it might be concluded that lactose replacement with other diluent will result in a tablet exhibiting either lower stability or inferior hardness.
Surprisingly, it has been found that lactose can be replaced with other diluent, a more stable product with all the assets of a high-grade tablet dosage form can be obtained, and thus the problem relating to Maillard's reaction with lactose can be solved accordingly.
The solution we propose provides a stable medicinal product in the tablet dosage form complying with all the requirements laid down on the orally administered medicines. In addition, these requirements are met over a wide range of concentrations of the excipients applied.